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1.  Haemoxygenase modulates cytokine induced neutrophil chemoattractant in hepatic ischemia reperfusion injury 
World Journal of Gastroenterology  2016;22(33):7518-7535.
AIM
To investigate the hepatic microcirculatory changes due to Haemoxygenase (HO), effect of HO inhibition on remote ischemic preconditioning (RIPC) and modulation of CINC.
METHODS
Eight groups of animals were studied - Sham, ischemia reperfusion injury (IRI) the animals were subjected to 45 min of hepatic ischemia followed by three hours of reperfusion, RIPC (remote ischemic preconditioning) + IRI group, remote ischemic preconditioning in sham (RIPC + Sham), PDTC + IR (Pyridodithiocarbamate, HO donor), ZnPP + RIPC + IRI (Zinc protoporphyrin prior to preconditioning), IR-24 (45 min of ischemia followed by 24 h of reperfusion), RIPC + IR-24 (preconditioning prior to IR). After 3 and 24 h of reperfusion the animals were killed by exsanguination and samples were taken.
RESULTS
Velocity of flow (160.83 ± 12.24 μm/s), sinusoidal flow (8.42 ± 1.19) and sinusoidal perfusion index (42.12 ± 7.28) in hepatic IR were lower (P < 0.05) in comparison to RIPC and PDTC (HO inducer). RIPC increased velocity of flow (328.04 ± 19.13 μm/s), sinusoidal flow (17.75 ± 2.59) and the sinusoidal perfusion index (67.28 ± 1.82) (P < 0.05). PDTC (HO induction) reproduced the effects of RIPC in hepatic IR. PDTC restored RBC velocity (300.88 ± 22.109 μm/s), sinusoidal flow (17.66 ± 3.71) and sinusoidal perfusion (82.33 ± 3.5) to near sham levels. ZnPP (HO inhibition) reduced velocity of flow of RBC in the RIPC group (170.74 ± 13.43 μm/s and sinusoidal flow in the RIPC group (9.46 ± 1.34). ZnPP in RIPC (60.29 ± 1.82) showed a fall in perfusion only at 180 min of reperfusion. Neutrophil adhesion in IR injury is seen in both postsinusoidal venules (769.05 ± 87.48) and sinusoids (97.4 ± 7.49). Neutrophil adhesion in RIPC + IR injury is reduced in both postsinusoidal venules (219.66 ± 93.79) and sinusoids (25.69 ± 9.08) (P < 0.05). PDTC reduced neutrophil adhesion in both postsinusoidal venules (89.58 ± 58.32) and sinusoids (17.98 ± 11.01) (P < 0.05) reproducing the effects of RIPC. ZnPP (HO inhibition) increased venular (589.04 ± 144.36) and sinusoidal neutrophil adhesion in preconditioned animals (121.39 ± 30.65) (P < 0.05). IR after 24 h of reperfusion increased venular and sinusoidal neutrophil adhesion in comparison to the early phase and was significantly reduced by RIPC. Hepatocellular cell death in IRI (80.83 ± 13.03), RIPC + IR (17.35 ± 2.47), and PTDC + IR (11.66 ± 1.17) reduced hepatocellular death. ZnPP + RIPC + IR (41.33 ± 3.07) significantly increased hepatocellular death (P < 0.05 PTDC/RIPC vs ZnPP and IR). The CINC cytokine levels in sham (101.32 ± 6.42). RIPC + sham (412.18 ± 65.24) as compared to sham (P < 0.05). CINC levels in hepatic IR were (644.08 ± 181.24). PDTC and RIPC CINC levels were significantly lower than hepatic IR (P < 0.05). HO inhibition in preconditioned animals with Zinc protoporphyrin increased serum CINC levels (521.81 ± 74.9) (P < 0.05). The serum CINC levels were high in the late phase of hepatic IR (15306 ± 1222.04). RIPC reduced CINC levels in the late phase of IR (467.46 ± 26.06), P < 0.05.
CONCLUSION
RIPC protects hepatic microcirculation by induction of HO and modulation of CINC in hepatic IR.
doi:10.3748/wjg.v22.i33.7518
PMCID: PMC5011667  PMID: 27672274
Reperfusion injury; CINC; Microcirculation; Ischemic preconditioning; Remote preconditioning; Haemoxygenase
2.  A Randomized Pilot Trial of Remote Ischemic Preconditioning in Heart Failure with Reduced Ejection Fraction 
PLoS ONE  2014;9(9):e105361.
Background
Remote ischemic preconditioning (RIPC) induced by transient limb ischemia confers multi-organ protection and improves exercise performance in the setting of tissue hypoxia. We aimed to evaluate the effect of RIPC on exercise capacity in heart failure patients.
Methods
We performed a randomized crossover trial of RIPC (4×5-minutes limb ischemia) compared to sham control in heart failure patients undergoing exercise testing. Patients were randomly allocated to either RIPC or sham prior to exercise, then crossed over and completed the alternate intervention with repeat testing. The primary outcome was peak VO2, RIPC versus sham. A mechanistic substudy was performed using dialysate from study patient blood samples obtained after sham and RIPC. This dialysate was used to test for a protective effect of RIPC in a mouse heart Langendorff model of infarction. Mouse heart infarct size with RIPC or sham dialysate exposure was also compared with historical control data.
Results
Twenty patients completed the study. RIPC was not associated with improvements in peak VO2 (15.6+/−4.2 vs 15.3+/−4.6 mL/kg/min; p = 0.53, sham and RIPC, respectively). In our Langendorff sub-study, infarct size was similar between RIPC and sham dialysate groups from our study patients, but was smaller than expected compared to healthy controls (29.0%, 27.9% [sham, RIPC] vs 51.2% [controls]. We observed less preconditioning among the subgroup of patients with increased exercise performance following RIPC (p<0.04).
Conclusion
In this pilot study of RIPC in heart failure patients, RIPC was not associated with improvements in exercise capacity overall. However, the degree of effect of RIPC may be inversely related to the degree of baseline preconditioning. These data provide the basis for a larger randomized trial to test the potential benefits of RIPC in patients with heart failure.
Trial Registration
ClinicalTrials.gov +++++NCT01128790
doi:10.1371/journal.pone.0105361
PMCID: PMC4152122  PMID: 25181050
3.  A randomized trial of remote ischemic preconditioning and control treatment for cardioprotection in sevoflurane-anesthetized CABG patients 
BMC Anesthesiology  2017;17:51.
Background
Remote ischemic preconditioning (RIPC) efficacy is debated. Possibly, because propofol, which has a RIPC-inhibiting action, is used in most RIPC trials. It has been suggested that clinical efficacy is, however, present with volatile anesthesia in the absence of propofol, although this is based on one phase 1 trial only. Therefore, in the present study we further explore the relation between RIPC and cardioprotection with perioperative anesthesia restricted to sevoflurane and fentanyl, in CABG patients without concomitant procedures.
Methods
In a single-center study, we aimed to randomize 46 patients to either RIPC (3x5 min inflation of a blood pressure cuff around the arm) or control treatment (deflated cuff around the arm). Blood samples were obtained before and after RIPC to evaluate potential RIPC-induced mediators (Interleukin (IL)-6, IL-10, Tumor Necrosis Factor-α, Macrophage Inhibitory Factor). An atrial tissue sample was obtained at cannulation of the appendix of the right atrium for determination of mitochondrial bound hexokinase II (mtHKII) and other survival proteins (Akt and AMP-activated protein kinase α). In blood samples taken before and 6, 12 and 24 h after surgery cardiac troponin T (cTnT) and C-reactive protein (CRP) were determined. Surgery was strictly performed under sevoflurane anesthesia (no propofol).
Results
We actually randomized 16 patients to control treatment and 13 patients to RIPC. The mean 24 h area under the curve (AUC) cTnT was 11.44 (standard deviation 4.66) in the control group and 10.90 (standard deviation 4.73) in the RIPC group (mean difference 0.54, 95% CI −3.06 to 4.13; p = 0.76). The mean 24 h AUC CRP was 1319 (standard deviation 92) in the control group and 1273 (standard deviation 141) in the RIPC group (mean difference 46.2, 95% CI −288 to 380; p = 0.78). RIPC was without effect on survival proteins in atrial tissue samples obtained before surgery (mitochondrial hexokinase, Akt and AMPK) and inflammatory mediators obtained before and immediately after RIPC (IL-6, IL-10, TNF-α, macrophage migration inhibitory factor).
Conclusion
Many factors can interfere with the outcome of RIPC. Trying to correct for this led to strict inclusion criteria, which, in combination with a decreased institutional frequency of CABG without concomitant procedures and a change in institutional anesthetic regimen away from volatile anesthetics towards total intravenous anesthesia, caused slow inclusion and halting of this trial after 3 years, before target inclusion could be reached. Therefore this study is underpowered to prove its primary goal that RIPC reduced AUC cTnT by < 25%. Nevertheless, we have shown that the effect of RIPC on 24 h AUC cTnT, in cardiac surgery with anesthesia during surgery restricted to sevoflurane/fentanyl (no propofol), was between a decrease of 27% and an increase of 36%. These findings are not in line with previous studies in this field.
Trial registration
The Netherlands Trial Register: NTR2915; Registered 25 Mei 2011.
doi:10.1186/s12871-017-0330-6
PMCID: PMC5372281  PMID: 28356068
4.  Plasma from human volunteers subjected to remote ischemic preconditioning protects human endothelial cells from hypoxia–induced cell damage 
Short repeated cycles of peripheral ischemia/reperfusion (I/R) can protect distant organs from subsequent prolonged I/R injury; a phenomenon known as remote ischemic preconditioning (RIPC). A RIPC-mediated release of humoral factors might play a key role in this protection and vascular endothelial cells are potential targets for these secreted factors. In the present study, RIPC-plasma obtained from healthy male volunteers was tested for its ability to protect human umbilical endothelial cells (HUVEC) from hypoxia–induced cell damage. 10 healthy male volunteers were subjected to a RIPC-protocol consisting of 4 × 5 min inflation/deflation of a blood pressure cuff located at the upper arm. Plasma was collected before (T0; control), directly after (T1) and 1 h after (T2) the RIPC procedure. HUVEC were subjected to 24 h hypoxia damage and simultaneously incubated with 5 % of the respective RIPC-plasma. Cell damage was evaluated by lactate dehydrogenase (LDH)-measurements. Western blot experiments of hypoxia inducible factor 1 alpha (HIF1alpha), phosphorylated signal transducer and activator of transcription 5 (STAT5), protein kinase B (AKT) and extracellular signal-related kinase 1/2 (ERK-1/2) were performed. Furthermore, the concentrations of hVEGF were evaluated in the RIPC-plasma by sandwich ELISA. Hypoxia–induced cell damage was significantly reduced by plasma T1 (p = 0.02 vs T0). The protective effect of plasma T1 was accompanied by an augmentation of the intracellular HIF1alpha (p = 0.01 vs T0) and increased phosphorylation of ERK-1/2 (p = 0.03 vs T0). Phosphorylation of AKT and STAT5 remained unchanged. Analysis of the protective RIPC-plasma T1 showed significantly reduced levels of hVEGF (p = 0.01 vs T0). RIPC plasma protects endothelial cells from hypoxia–induced cell damage and humoral mediators as well as intracellular HIF1alpha may be involved.
doi:10.1007/s00395-015-0474-9
PMCID: PMC4341024  PMID: 25716080
Remote conditioning; Human endothelium; Signalling kinases; Translational study
5.  Remote ischemic preconditioning triggers changes in autonomic nervous system activity: implications for cardioprotection 
Physiological Reports  2017;5(3):e13085.
Abstract
Cardioprotective efficacy of remote ischemic preconditioning (RIPC) remains controversial. Experimental studies investigating RIPC have largely monitored cardiovascular changes during index ischemia and reperfusion with little work investigating changes during RIPC application. This work aims to identify cardiovascular changes associated with autonomic nervous system (ANS) activity during RIPC and prior to index ischemia. RIPC was induced in anesthetized male C57/Bl6 mice by four cycles of 5 min of hindlimb ischemia using inflated cuff (200 mmHg) followed by 5 min reperfusion. Electrocardiography (ECG) and microcirculatory blood flow in both hindlimbs were recorded throughout RIPC protocol. Heart rate variability (HRV) analysis was performed using ECG data. Hearts extracted at the end of RIPC protocol were used either for measurement of myocardial metabolites using high‐performance liquid chromatography or for Langendorff perfusion to monitor function and injury during 30 min index ischemia and 2 h reperfusion. Isolated‐perfused hearts from RIPC animals had significantly less infarct size after index ischemia and reperfusion (34 ± 5% vs. 59 ± 7%; mean ± SE P < 0.05). RIPC protocol was associated with increased heart rate measured both in ex vivo and in vivo. Frequency ratio of HRV spectra was altered in RIPC compared to control. RIPC was associated with a standard hyperemic response in the cuffed‐limb but there was a sustained reduction in blood flow in the uncuffed contralateral limb. RIPC hearts (prior to index ischemia) had significantly lower phosphorylation potential and energy charge compared to the control group. In conclusion, RIPC is associated with changes in ANS activity (heart rate, blood flow, HRV) and mild myocardial ischemic stress that would contribute to cardioprotection.
doi:10.14814/phy2.13085
PMCID: PMC5309573  PMID: 28193783
Autonomic nervous system; blood flow; cardiac; ischemia; remote ischemic preconditioning
6.  The Impact of Remote Ischemic Pre-Conditioning on Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography and Angioplasty: A Double-Blind Randomized Clinical Trial 
Electronic Physician  2015;7(8):1557-1565.
Background and objective
Contrast-induced nephropathy (CIN) is an acute major complication following intravascular administration of iodinated contrast agents; however, the best approach for preventing CIN is not clear. Remote ischemic pre-conditioning (RIPC) is a new, non-pharmacological method that has been considered for the prevention of CIN following coronary angiography. This study assessed the effects of RIPC with four brief episodes of upper limb ischemia and reperfusion in the prevention of contrast-induced nephropathy (CIN) after coronary angiography and/or angioplasty.
Methods
In this double-blind randomized clinical trial, we enrolled 51 patients with chronic stable angina and non-ST elevation acute coronary syndrome (NSTE.ACS), and they underwent coronary angiography and/or angioplasty. Standard fluid therapy with normal saline was prescribed for all patients before and after the procedure. The patients were divided into two groups, i.e., a study group of patients who had undergone RIPC intervention and a control group of patients who had not undergone RIPC. One hour before the procedure, a sphygmomanometer cuff was placed around one arm and inflated up to 50 mmHg above the systolic pressure for five minutes; then, the cuff was deflated for another five minutes, and this cycle was repeated four times. The patients’ serum creatinine levels were measured at baseline and 48 hours after the procedure, and the incidence of CIN was calculated.
Results
Twenty-one males and 30 females were studied in two groups, i.e., an RIPC intervention group (n = 25) and a control group (n = 26) that were homogenous considering baseline characteristics. No significant difference was observed in the mean level of serum creatinine between the two groups at a post-intervention time of 48 hours (RICP: 1.74 ± 0.70 mg/dL vs. Control: 1.75 ± 0.87 mg/dL; P = 0.64). However, a lower incidence rate of CIN was observed 48 hours after the administration of the contrast medium in the RIPC group, but it was not statistically significant (RIPC: 23.1% vs. Control: 12.0%; P = 0.30).
Conclusion
It seems that adequate fluid therapy is still the most effective strategy for preventing CIN and that RIPC might have additional protective effects in very high risk patients, such as those with severe renal insufficiency and heart failure.
doi:10.19082/1557
PMCID: PMC4725407  PMID: 26816582
percutaneous coronary intervention; coronary angiography; kidney diseases; contrast-induced nephropathy; remote ischemic pre-conditioning
7.  Remote ischaemic preconditioning down-regulates kinin receptor expression in neutrophils of patients undergoing heart surgery 
OBJECTIVES
Remote ischaemic preconditioning (RIPC) may protect distant organs against ischaemia-reperfusion injury. We investigated the impact of RIPC on kinin receptor expression in neutrophils following RIPC in patients undergoing coronary artery bypass grafting (CABG).
METHODS
Patients undergoing elective CABG with cardiopulmonary bypass (CPB) were randomized to RIPC (n = 15) or control (n = 15) groups. The study group underwent RIPC by inflation of a blood pressure cuff on the arm. Expression of kinin receptors, plasma concentrations of IL-6, IL-8, IL-10, TNF-α and neutrophil elastase were determined at baseline (before RIPC/sham), immediately before surgery (after RIPC/sham) and 30 min and 24 h after surgery. Plasma bradykinin levels were assessed before and after RIPC/sham, and at 30 min, 6, 12 and 24 h after surgery. Serum creatine kinase (CK), troponin I, C-reactive protein (CRP) and lactate levels were measured immediately prior to surgery and 30 min, 6, 12, 24 and 48 h after surgery.
RESULTS
Kinin B2 receptor expression did not differ between the groups at baseline (pre-RIPC), but was significantly lower in the RIPC group than in the control group after RIPC/sham (P < 0.05). Expressions of both kinin B1 and B2 receptors were significantly down-regulated in the RIPC group, and this persisted to 24 h after surgery (P < 0.001). Neutrophil elastase levels were significantly increased after surgery. There were no differences in CK, CRP, cytokine, lactate or troponin I levels between the groups.
CONCLUSIONS
RIPC down-regulated the expression of kinin B1 and B2 receptors in neutrophils of patients undergoing CABG.
doi:10.1093/icvts/ivt279
PMCID: PMC3781800  PMID: 23814135
Bradykinin; Ischaemia; Ischaemic preconditioning; Kinin receptors; Cardiac surgery
8.  Characterization of acute ischemia‐related physiological responses associated with remote ischemic preconditioning: a randomized controlled, crossover human study 
Physiological Reports  2014;2(11):e12200.
Abstract
Remote Ischemic Preconditioning (RIPC) is emerging as a new noninvasive intervention that has the potential to protect a number of organs against ischemia–reperfusion (IR) injury. The standard protocols normally used to deliver RIPC involve a number of cycles of inflation of a blood pressure (BP) cuff on the arm and/or leg to an inflation pressure of 200 mmHg followed by cuff deflation for a short period of time. There is little evidence to support what limb (upper or lower) or cuff inflation pressures are most effective to deliver this intervention without causing undue discomfort/pain in nonanesthetized humans. In this preliminary study, a dose–response assessment was performed using a range of cuff inflation pressures (140, 160, and 180 mmHg) to induce limb ischemia in upper and lower limbs. Physiological changes in the occluded limb and any pain/discomfort associated with RIPC with each cuff inflation pressure were determined. Results showed that ischemia can be induced in the upper limb at much lower cuff inflation pressures compared with the standard 200 mmHg pressure generally used for RIPC, provided the cuff inflation pressure is ~30 mmHg higher than the resting systolic BP. In the lower limb, a higher inflation pressure, (~55 mmHg > resting systolic BP), is required to induce ischemia. Cyclical changes in capillary blood O2, CO2, and lactate levels during the RIPC stimulus were observed. RIPC at higher cuff inflation pressures of 160 and 180 mmHg was better tolerated in the upper limb. In summary, limb ischemia for RIPC can be more easily induced at lower pressures and is much better tolerated in the upper limb in young healthy individuals. However, whether benefits of RIPC can also be derived with protocols delivered to the upper limb using lower cuff inflation pressures and with lesser discomfort compared to the lower limb, remains to be investigated.
Remote Ischemic Preconditioning (RIPC) is emerging as a new noninvasive intervention that has the potential to protect a number of organs against ischemia‐reperfusion (IR) injury. Currently, there is little evidence to support what limb (upper or lower) or cuff inflation pressures are most effective to deliver this intervention without causing undue discomfort/pain in nonanesthetized humans. In this study we have demonstrated that limb ischemia for RIPC can be more easily induced at lower pressures and is much better tolerated in the upper limb compared with the lower limb, in young healthy individuals.
doi:10.14814/phy2.12200
PMCID: PMC4255807  PMID: 25413320
Characterization; cuff inflation pressure; remote ischemic preconditioning; tolerability
9.  Repeated remote ischemic preconditioning and isoflurane anesthesia in an experimental model of renal ischemia-reperfusion injury 
BMC Anesthesiology  2017;17:14.
Background
In animal studies, remote ischemic preconditioning (RIPC) and anesthetic preconditioning are successful in reducing renal ischemia reperfusion injury (IRI), however the protective effect of RIPC may be improved by repeating the RIPC stimulus.
Methods
Sprague-Dawley rats underwent unilateral nephrectomy followed by 30 min of renal pedicle clamping. Animals were allocated into six groups: sham, control (IRI), RepISO (daily isoflurane anesthesia), RIPC (single dose isoflurane anesthesia and single dose RIPC), RepISO + RIPC (7-day isoflurane anesthesia and single dose RIPC) and RepISO + RepRIPC (7-day isoflurane anesthesia with 7-day RIPC). RIPC was applied by 3×5 min of cuff inflation on both thighs. Serum creatinine and urea levels were measured and histology was obtained at day two.
Results
RepISO diminished renal IRI, as reflected by a significant reduction in serum creatinine levels as compared to the control group, 170 ± 74 resp. 107 ± 29 μmol/L. The other preconditioning protocols showed similar reduction in serum creatinine levels as compared to the control group. No significant differences were observed between the different preconditioning protocols. For urea levels, only RepISO + RIPC resulted in significantly lower levels as compared to the control group, 14 ± 4 resp. 22 ± 7 mmol/L (p = 0.010). In the preconditioning groups only RepISO showed less histological damage as compared to controls 1.73 ± 1.19 resp. 2.91 ± 1.22 (p = 0.032).
Conclusions
In this study no additional protective effect of repeated ischemic preconditioning was observed as compared to single dose RIPC. Repeated administration of isoflurane provided stronger protection against renal IRI as compared to single dose isoflurane.
doi:10.1186/s12871-017-0310-x
PMCID: PMC5273799  PMID: 28129737
Anesthetic preconditioning; Animal experiment; Ischemia reperfusion injury; Kidney; Repeated remote ischemic preconditioning
10.  Cardioprotective effect of remote preconditioning of trauma and remote ischemia preconditioning in a rat model of myocardial ischemia/reperfusion injury 
Remote ischemia preconditioning (RIPC) and remote preconditioning of trauma (RPCT) are two methods used to induce a cardioprotective function against ischemia/reperfusion injury (IRI). However, the underlying mechanisms of these two methods differ. The aim of the present study was to investigate the cardioprotective function of the two methods, and also observe whether combining RIPC with RPCT enhanced the protective effect. In total, 70 male Sprague Dawley rats were randomly divided into five groups, which included the sham, control, RIPC + RPCT, RPCT and RIPC groups. With the exception of the sham group, all the rats were subjected to myocardial IRI through the application of 30 min occlusion of the left coronary artery and 180 min reperfusion. Serum cardiac troponin I (cTnI) levels, myocardial infarct size (IS) and the cardiomyocyte apoptotic index (AI) were assessed. The levels of serum cTnI were lower in the experimental groups when compared with the control group (control, 58.59±12.50 pg/ml; RIPC + RPCT, 46.05±8.62 pg/ml; RPCT, 45.98±11.24 pg/ml; RIPC, 43.46±5.05 pg/ml; P<0.05, vs. control), and similar results were observed for the myocardial IS (control, 48.34±6.79%; RIPC + RPCT, 29.64±4.51%; RPCT, 29.05±8.51%; RIPC, 27.72±6.27%; P<0.05, vs. control) and the AI (control, 31.75±10.65%; RIPC + RPCT, 18.32±9.30%; RPCT, 18.51±9.26%; RIPC, 20.41±3.86%; P<0.05, vs. control). However, no statistically significant differences were observed among the three experimental groups (P>0.05). Therefore, RIPC and RPCT exhibit cardioprotective effects when used alone or in combination. However, a combination of RIPC and RPCT does not enhance the cardioprotective effect observed with the application of either single method. Therefore, for patients undergoing major abdominal surgery, RIPC was considered to be unnecessary, while for patients undergoing other types of non-cardiac major surgery and minimally invasive interventional surgery, RIPC may be useful. In addition, patients with embolism diseases are also liable to IRI when reperfusion treatment such as thrombolysis is conducted. Thus RIPC may also be beneficial for these patients.
doi:10.3892/etm.2015.2320
PMCID: PMC4471708  PMID: 26136887
ischemia/reperfusion injury; ischemia preconditioning; remote ischemia preconditioning; remote preconditioning of trauma; myocardioprotection
11.  Apolipoprotein A-I Is a Potential Mediator of Remote Ischemic Preconditioning 
PLoS ONE  2013;8(10):e77211.
Background
Remote ischemic preconditioning (RIPC) has emerged as an attractive strategy in clinical settings. Despite convincing evidence of the critical role played by circulating humoral mediators, their actual identities remain unknown. In this study, we aimed to identify RIPC-induced humoral mediators using a proteomic approach.
Methods
and Results Rats were exposed to 10-min limb ischemia followed by 5- (RIPC 5′) or 10-min (RIPC 10′) reperfusion prior to blood sampling. The control group only underwent blood sampling. Plasma samples were analyzed using surface-enhanced laser desorption and ionization - time of flight - mass spectrometry (SELDI-TOF-MS). Three protein peaks were selected for their significant increase in RIPC 10′. They were identified and confirmed as apolipoprotein A-I (ApoA-I). Additional rats were exposed to myocardial ischemia-reperfusion (I/R) and assigned to one of the following groups RIPC+myocardial infarction (MI) (10-min limb ischemia followed by 10-min reperfusion initiated 20 minutes prior to myocardial I/R), ApoA-I+MI (10 mg/kg ApoA-I injection 10 minutes before myocardial I/R), and MI (no further intervention). In comparison with untreated MI rats, RIPC reduced infarct size (52.2±3.7% in RIPC+MI vs. 64.9±2.6% in MI; p<0.05). Similarly, ApoA-I injection decreased infarct size (50.9±3.8%; p<0.05 vs. MI).
Conclusions
RIPC was associated with a plasmatic increase in ApoA-I. Furthermore, ApoA-I injection before myocardial I/R recapitulated the cardioprotection offered by RIPC in rats. This data suggests that ApoA-I may be a protective blood-borne factor involved in the RIPC mechanism.
doi:10.1371/journal.pone.0077211
PMCID: PMC3796499  PMID: 24155931
12.  Profiling of cell stress protein expression in cardiac tissue of cardiosurgical patients undergoing remote ischemic preconditioning: implications for thioredoxin in cardioprotection 
Background
Transient episodes of ischemia in a remote organ (remote ischemic preconditioning, RIPC) can attenuate myocardial ischemia/reperfusion injury but the underlying mechanisms of RIPC in the target organ are still poorly understood. Recent animal studies suggested that the small redox protein thioredoxin may be a potential candidate for preconditioning-induced organprotection. Here we employed a human proteome profiler array to investigate the RIPC regulated expression of cell stress proteins and particularly of thioredoxin in heart tissue of cardiosurgical patients with cardiopulmonary bypass (CPB).
Methods
RIPC was induced by four 5 minute cycles of transient upper limb ischemia/reperfusion using a blood pressure cuff. Right atrial tissue was obtained from patients receiving RIPC (N = 19) and control patients (N = 19) before and after CPB. Cell stress proteome profiler arrays as well as Westernblotting and ELISA experiments for thioredoxin (Thio-1) were performed employing the respective tissue samples.
Results
Protein arrays revealed an up-regulation of 26.9% (7/26; CA IX, Cyt C, HSP-60, HSP-70, pJNK, SOD2, Thio-1) of cell stress associated proteins in RIPC tissue obtained before CPB, while 3.8% (1/26; SIRT2) of the proteins were down-regulated. Array results for thioredoxin were verified by semi-quantitative Westernblotting studies which showed a significant up-regulation of thioredoxin protein levels in cardiac tissue samples of RIPC patients taken before CPB (RIPC: 5.36 ± 0.85 a.u.; control: 3.23 ± 0.39 a.u.; P < 0.05). Quantification of thioredoxin levels in tissue of RIPC and control patients by ELISA experiments further confirmed the Westernblotting results (RIPC: 0.30 ± 0.02 ng/mg protein; control: 0.24 ± 0.02 ng/mg protein; P < 0.05).
Conclusion
We provide evidence for thioredoxin as a RIPC-induced factor in heart tissue of cardiosurgical patients and identified several cell stress associated proteins that are regulated by RIPC and may play a role in RIPC-mediated cardioprotection.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-015-0403-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12967-015-0403-6
PMCID: PMC4316390  PMID: 25622749
Remote ischemic preconditioning; Cardioprotection; Cardiac surgery; Protein expression; Thioredoxin
13.  Increased C reactive protein and cardiac enzyme levels after coronary stent implantation. Is there protection by remote ischaemic preconditioning? 
Heart  2006;92(12):1821-1826.
Aim
To investigate whether remote ischaemic preconditioning (RIPC) can attenuate the inflammatory response and enzyme leakage that can occur after uncomplicated routine percutaneous coronary intervention (PCI).
Methods
41 consecutive normotensive patients with stable angina and single‐vessel disease were assigned to be exposed to RIPC (n = 20) or not (control group; n = 21) before elective PCI with stent implantation. RIPC was induced by three cycles of 5‐min ischaemia–reperfusion of both upper limbs (inflation/deflation of blood pressure cuff). C reactive protein (CRP), creatine phosphokinase (CK), CK cardiac isoenzyme (CK‐MB) and troponin I (TNI) were serially measured for 48 h.
Results
No difference in baseline values was observed between the groups. The CRP rose significantly (p<0.001) and at 48 h was similarly increased (>fourfold) in both groups (15.7 (2.6) v 14.0 (3.3) mg/l, RIPC v control; p = NS). However, sub‐group analysis on the basis of statin use showed that the highest rise was in the group of patients with RIPC not taking statins and was significantly greater than in patients with RIPC taking statins (23.8 (3.71) v 11.4 (3.0) mg/l, respectively, p<0.01). Both CK‐MB and TNI leakage were raised (slightly but significantly) after PCI in controls at 24 h compared with baseline values. However, this small rise was significantly worse after RIPC (CK‐MB, 1.33 (0.27) v 3.57 (0.97) ng/ml, p<0.01; TNI, 0.255 (0.059) v 0.804 (0.232) ng/ml, p<0.05, respectively at 24 h). The increase was more marked in the RIPC subgroup not taking statins.
Conclusions
RIPC does not reduce, but exacerbates, the enzyme and TNI release from the heart after single‐vessel angioplasty with stent. Furthermore, the increased circulating CRP remains raised. It seems that there is an enhanced inflammatory response after RIPC in the absence of statin treatment.
doi:10.1136/hrt.2006.089060
PMCID: PMC1861265  PMID: 16855045
14.  Remote ischemic preconditioning in patients with intermittent claudication 
Clinics  2013;68(4):495-499.
OBJECTIVE:
Remote ischemic preconditioning (RIPC) is a phenomenon in which a short period of sub-lethal ischemia in one organ protects against subsequent bouts of ischemia in another organ. We hypothesized that RIPC in patients with intermittent claudication would increase muscle tissue resistance to ischemia, thereby resulting in an increased ability to walk.
METHODS:
In a claudication clinic, 52 ambulatory patients who presented with complaints of intermittent claudication in the lower limbs associated with an absent or reduced arterial pulse in the symptomatic limb and/or an ankle-brachial index <0.90 were recruited for this study. The patients were randomly divided into three groups (A, B and C). All of the patients underwent two tests on a treadmill according to the Gardener protocol. Group A was tested first without RIPC. Group A was subjected to RIPC prior to the second treadmill test. Group B was subjected to RIPC prior to the first treadmill test and then was subjected to a treadmill test without RIPC. In Group C (control group), both treadmill tests were performed without RIPC. The first and second tests were conducted seven days apart. Brazilian Clinical Trials: RBR-7TF6TM.
RESULTS:
Group A showed a significant increase in the initial claudication distance in the second test compared to the first test.
CONCLUSION:
RIPC increased the initial claudication distance in patients with intermittent claudication; however, RIPC did not affect the total walking distance of the patients.
doi:10.6061/clinics/2013(04)10
PMCID: PMC3634960  PMID: 23778346
Intermittent Claudication; Ischemic Preconditioning; Peripheral Arterial Disease
15.  Cardiac Phosphoproteomics during Remote Ischemic Preconditioning: A Role for the Sarcomeric Z-Disk Proteins 
BioMed Research International  2014;2014:767812.
Remote ischemic preconditioning (RIPC) induced by brief ischemia/reperfusion cycles of remote organ (e.g., limb) is cardioprotective. The myocardial cellular changes during RIPC responsible for this phenomenon are not currently known. The aim of this work was to identify the activation by phosphorylation of cardiac proteins following RIPC. To achieve our aim we used isobaric tandem mass tagging (TMT) and reverse phase nanoliquid chromatography tandem spectrometry using a Linear Trap Quadropole (LTQ) Orbitrap Velos mass spectrometer. Male C57/Bl6 mice were anesthetized by an intraperitoneal injection of Tribromoethanol. A cuff was placed around the hind limb and inflated at 200 mmHg to prevent blood flow as confirmed by Laser Doppler Flowmetry. RIPC was induced by 4 cycles of 5 min of limb ischemia followed by 5 min of reperfusion. Hearts were extracted for phosphoproteomics. We identified approximately 30 phosphoproteins that were differentially expressed in response to RIPC protocol. The levels of several phosphoproteins in the Z-disk of the sarcomere including phospho-myozenin-2 were significantly higher than control. This study describes and validates a novel approach to monitor the changes in the cardiac phosphoproteome following the cardioprotective intervention of RIPC and prior to index ischemia. The increased level of phosphorylated sarcomeric proteins suggests they may have a role in cardiac signaling during RIPC.
doi:10.1155/2014/767812
PMCID: PMC3985148  PMID: 24795895
16.  MicroRNA-29a/b/c targets iNOS and is involved in protective remote ischemic preconditioning in an ischemia-reperfusion rat model of non-alcoholic fatty liver disease 
Oncology Letters  2017;13(3):1775-1782.
Remote ischemic preconditioning (RIPC) protects against the injury that is incurred by ischemia and reperfusion (IR); however, the role of RIPC in liver IR injury in non-alcoholic fatty liver disease (NAFLD) remains unclear. In this study, a NAFLD rat model was utilized in a series of different surgical procedures and molecular experiments. Rats of the IR group and the RIPC+IR group exhibited more severe injury than NAFLD control rats (in which the liver was prodded following a median-incision laparotomy). The liver condition, measured by serum alanine transaminase and aspartate transaminase levels, of the RIPC+IR group was better than that of the IR group. In addition, alanine transaminase and aspartate transaminase levels were lower in the RIPC+IR group compared with the IR group (P<0.001). Flow cytometry revealed that the cell apoptosis ratio was significantly lower in the RIPC+IR group than in the IR group (P<0.001). Reverse transcription-polymerase chain reaction (RT-qPCR) was used to assess miR-29a/b/c levels, revealing that they were significantly reduced in the RIPC and RIPC+IR groups, but did not vary in the IR group compared with the control group. RT-qPCR also revealed that iNOS mRNA levels were not significantly different among any of the NAFLD groups; however, western blot analysis indicated that iNOS protein levels were increased in the RIPC group and the RIPC+IR group compared with the control and IR groups. A luciferase reporter assay demonstrated that transfection with miR-29a/b/c mimics significantly decreased the luciferase activities of plasmids containing the wild-type iNOS 3′-untranslated region (UTR) (relative fluorescence intensity: 0.47±0.06 for miR-29a, 0.36±0.07 for miR-29b, 0.41±0.04 for miR-29c; P<0.001), whereas the activities of plasmids containing the mutant iNOS 3′-UTR sequence were not markedly affected [relative fluorescence intensity: 0.99±0.08 for miR-29a (P=0.1349), 0.99±0.09 for miR-29b (P=0.1607), 0.97±0.07 for miR-29c (P=0.1824)]. This suggested that miR-29a/b/c downregulates iNOS by directly targeting its 3′-UTR. In summary, the results suggest that RIPC has a protective effect in NAFLD liver IR injury, which may be due to reduced miR-29a/b/c levels in the skeletal muscle, leading to increased iNOS and, therefore, nitric oxide.
doi:10.3892/ol.2017.5623
PMCID: PMC5403535
remote ischemic preconditioning; microRNA-29a/b/c; inducible nitric oxide synthase; non-alcoholic fatty liver disease
17.  Remote ischemic preconditioning preserves Connexin 43 phosphorylation in the rat heart in vivo 
Background
Remote ischemic preconditioning (RIPC) protects the heart from ischemia and reperfusion (I/R) injury. The underlying molecular mechanisms are unclear. It has been demonstrated that Connexin 43 (Cx43) is critically involved in cardioprotective interventions including classical ischemic preconditioning. In the present study we investigated the influence of RIPC on the expression patterns of Cx43 after I/R in the rat heart in vivo.
Methods
Male Wistar rats were subjected to 35 min regional myocardial ischemia followed by 2 h reperfusion with or without 4 cycles of 5 minutes bilateral hind limb ischemia and reperfusion (RIPC), to RIPC without ischemia or underwent no intervention (Sham). Infarct size was measured by TTC staining. The myocardium was divided into area at risk (AAR) and area not at risk (non AAR). Expression of Cx43-mRNA and protein was analyzed by qPCR and Western Blot analysis, respectively. Localization of Cx43 was visualized by confocal immunofluorescence staining.
Results
RIPC reduced the infarct size (I/R: 73 ± 5% vs. RIPC I/R: 34 ± 14%, p < 0.05). Expression of Cx43 mRNA did not differ between groups. I/R caused a strong decrease of relative Cx43 protein expression in the AAR that was partly abolished by RIPC. Furthermore, RIPC decreased the level of ischemia-induced dephosphorylation of Cx43. Confocal immunofluorescence staining showed that I/R caused a loss of the Cx43 signal at the intercalated discs, while the Cx43 signal at the intercalated discs was partly sustained after RIPC.
Conclusion
Preservation of Cx43 protein expression and phosphorylation after RIPC might protect the rat heart in vivo.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-014-0228-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12967-014-0228-8
PMCID: PMC4256705  PMID: 25159820
Cardioprotection; Connexin 43 (Cx43); Remote ischemic preconditioning (RIPC)
18.  Cardiac Remote Ischemic Preconditioning Prior to Elective Vascular Surgery (CRIPES): A Prospective, Randomized, Sham‐Controlled Phase II Clinical Trial 
Background
Remote ischemic preconditioning (RIPC) has been shown to reduce infarct size in animal models. We hypothesized that RIPC before an elective vascular operation would reduce the incidence and amount of a postoperative rise of the cardiac troponin level.
Methods and Results
Cardiac Remote Ischemic Preconditioning Prior to Elective Vascular Surgery (CRIPES) was a prospective, randomized, sham‐controlled phase 2 trial using RIPC before elective vascular procedures. The RIPC protocol consisted of 3 cycles of 5‐minute forearm ischemia followed by 5 minutes of reperfusion. The primary endpoint was the proportion of subjects with a detectable increase in cardiac troponin I (cTnI) and the distribution of such increases. From June 2011 to September 2015, 201 male patients (69±7, years) were randomized to either RIPC (n=100) or a sham procedure (n=101). Indications for vascular surgery included an expanding abdominal aortic aneurysm (n=115), occlusive peripheral arterial disease of the lower extremities (n=37), or internal carotid artery stenosis (n=49). Of the 201 patients, 47 (23.5%) had an increase in cTnI above the upper reference limit within 72 hours of the vascular operation, with no statistically significant difference between those patients assigned to RIPC (n=22; 22.2%) versus sham procedure (n=25; 24.7%; P=0.67). Among the cohort with increased cTnI, the median peak values (interquartile range) in the RIPC and control group were 0.048 (0.004–0.174) and 0.017 (0.003–0.105), respectively (P=0.54).
Conclusions
In this randomized, controlled trial of men with increased perioperative cardiac risks, elevation in cardiac troponins was common following vascular surgery, but was not reduced by a strategy of RIPC.
Clinical Trial Registration
URL: https://www.clinicaltrials.gov. Unique identifier: NCT01558596.
doi:10.1161/JAHA.116.003916
PMCID: PMC5121495  PMID: 27688236
remote preconditioning; troponins; vascular surgery; Translational Studies; Peripheral Vascular Disease; Vascular Disease
19.  Kinetics and Signal Activation Properties of Circulating Factor(s) From Healthy Volunteers Undergoing Remote Ischemic Pre-Conditioning 
Summary
Although remote ischemic pre-conditioning (RIPC) reduced infarct size in animal experiments and proof-of-concept clinical trials, recent phase III trials failed to confirm cardioprotection during cardiac surgery. Here, we characterized the kinetic properties of humoral factors that are released after RIPC, as well as the signal transduction pathways that were responsible for cardioprotection in an ex vivo model of global ischemia reperfusion injury. Venous blood from 20 healthy volunteers was collected at baseline and 5 min, 30 min, 1 h, 6 h, and daily from 1 to 7 days after RIPC (3 × 5/5 min upper-limb ischemia/reperfusion). Plasma-dialysates (cut-off: 12 to 14 kDa; dilution: 1:20) were infused into Langendorff-perfused mouse hearts subjected to 20/120 min global ischemia/reperfusion. Infarct size and phosphorylation of signal transducer and activator of transcription (STAT)3, STAT5, extracellular-regulated kinase 1/2 and protein kinase B were determined. In a subgroup of plasma-dialysates, an inhibitor of STAT3 (Stattic) was used in mouse hearts. Perfusion with baseline-dialysate resulted in an infarct size of 39% of ventricular mass (interquartile range: 36% to 42%). Perfusion with dialysates obtained 5 min to 6 days after RIPC significantly reduced infarct size by ∼50% and increased STAT3 phosphorylation beyond that with baseline-dialysate. Inhibition of STAT3 abrogated these effects. These results suggest that RIPC induces the release of cardioprotective, dialyzable factor(s) within 5 min, and that circulate for up to 6 days. STAT3 is activated in murine myocardium by RIPC-induced human humoral factors and is causally involved in cardioprotection.
Visual Abstract
Highlights
•Pre-clinical and early phase clinical studies with remote ischemic preconditioning (RIPC) appeared promising; however, RIPC was not effective in phase III clinical trials.•To improve the translation of RIPC into clinical practice, the kinetic properties and functional effects of humoral factors released after RIPC in humans were characterized ex vivo.•Venous blood from 20 healthy volunteers was collected at baseline and 5 min, 30 min, 1 h, 6 h and daily from 1 to 7 days after RIPC. Plasma dialysates were infused into Langendorff-perfused mouse hearts subjected to 20/120 min global ischemia/reperfusion.•Perfusion with dialysates obtained 5 min to 6 days after RIPC significantly reduced infarct size by ∼50% when compared to perfusion with dialysates obtained at baseline prior to RIPC, and increased STAT3 phosphorylation beyond values obtained with baseline-dialysate.
doi:10.1016/j.jacbts.2016.01.007
PMCID: PMC5012372  PMID: 27642642
cardioprotection; human; humoral factor; kinetics; remote ischemic pre-conditioning; signaling; AKT, protein kinase B; ERK, extracellular-regulated kinase; IQR, interquartile range; LV+RV, left and right ventricular; LVDP, left ventricular developed pressure; RIC, remote ischemic conditioning; RIPC, remote ischemic pre-conditioning; SAFE, survival activating factor enhancement; STAT, signal transducer and activator of transcription; TTC, 2,3,5-triphenyltetrazolium chloride
20.  Preconditioning Shields Against Vascular Events in Surgery (SAVES), a multicentre feasibility trial of preconditioning against adverse events in major vascular surgery: study protocol for a randomised control trial 
Trials  2015;16:185.
Background
Patients undergoing vascular surgery procedures constitute a ‘high-risk’ group. Fatal and disabling perioperative complications are common. Complications arise via multiple aetiological pathways. This mechanistic redundancy limits techniques to reduce complications that target individual mechanisms, for example, anti-platelet agents. Remote ischaemic preconditioning (RIPC) induces a protective phenotype in at-risk tissue, conferring protection against ischaemia-reperfusion injury regardless of the trigger. RIPC is induced by repeated periods of upper limb ischaemia-reperfusion produced using a blood pressure cuff. RIPC confers some protection against cardiac and renal injury during major vascular surgery in proof-of-concept trials. Similar trials suggest benefit during cardiac surgery. Several uncertainties remain in advance of a full-scale trial to evaluate clinical efficacy. We propose a feasibility trial to fully evaluate arm-induced RIPC’s ability to confer protection in major vascular surgery, assess the incidence of a proposed composite primary efficacy endpoint and evaluate the intervention’s acceptability to patients and staff.
Methods/Design
Four hundred major vascular surgery patients in five Irish vascular centres will be randomised (stratified for centre and procedure) to undergo RIPC or not immediately before surgery. RIPC will be induced using a blood pressure cuff with four cycles of 5 minutes of ischaemia followed by 5 minutes of reperfusion immediately before the start of operations. There is no sham intervention. Participants will undergo serum troponin measurements pre-operatively and 1, 2, and 3 days post-operatively. Participants will undergo 12-lead electrocardiograms pre-operatively and on the second post-operative day. Predefined complications within one year of surgery will be recorded. Patient and staff experiences will be explored using qualitative techniques. The primary outcome measure is the proportion of patients who develop elevated serum troponin levels in the first 3 days post-operatively. Secondary outcome measures include length of hospital and critical care stay, unplanned critical care admissions, death, myocardial infarction, stroke, mesenteric ischaemia and need for renal replacement therapy (within 30 days of surgery).
Discussion
RIPC is novel intervention with the potential to significantly improve perioperative outcomes. This trial will provide the first evaluation of RIPC’s ability to reduce adverse clinical events following major vascular surgery.
Trial Registration
www.clinicaltrials.gov NCT02097186 Date Registered: 24 March 2014
doi:10.1186/s13063-015-0678-1
PMCID: PMC4414457  PMID: 25903752
remote preconditioning; vascular surgery; perioperative complications
21.  Remote Ischemic Preconditioning for the Prevention of Contrast-Induced Acute Kidney Injury in Diabetics Receiving Elective Percutaneous Coronary Intervention 
PLoS ONE  2016;11(10):e0164256.
Objective
Remote ischemic preconditioning (RIPC) induces transient episodes of ischemia by the occlusion of blood flow in non-target tissue, before a subsequent ischemia-reperfusion injury. When RIPC is applied before percutaneous coronary intervention (PCI), the kidneys may be protected against ischemia-reperfusion injury and subsequently contrast-induced acute kidney injury (CI-AKI). The aim of this study was to evaluate the efficacy of RIPC for the prevention of CI-AKI in patients with diabetes with pre-existing chronic kidney disease (CKD) undergoing elective PCI.
Methods
This randomized, double-blind, sham-controlled study enrolled patients with diabetes scheduled for elective PCI with eGFR ≤60 ml/min/1.73 m2 or urinary albumin creatinine ratio of >300 mg/g to receive either RIPC or the sham ischemic preconditioning.
Results
One hundred and two patients (68.9 ± 8.2 years old, 47.1% men) were included. Baseline eGFR, creatinine and serum NGAL was similar between RIPC and control groups (48.5 ± 12 ml/min vs. 46.6 ± 10 ml/min, p = 0.391; 1.42 ± 0.58 mg/dl vs. 1.41 ± 0.34 mg/dl, p = 0.924; and 136.0 ± 45.0 ng/ml vs. 137.6 ± 43.3 ng/ml, p = 0.961, respectively). CI-AKI occurred in 13.7% (14/102) of the total subjects, with both RIPC and control groups having an equal incidence of 13.7% (7/51). No significant differences were seen in creatinine, NGAL, cardiac enzymes (troponin T, CKMB) and hs-CRP between the groups post-procedure.
Conclusions
In this study, RIPC applied prior to elective PCI was not effective in preventing CI-AKI in patients with diabetes with pre-existing CKD.
Trial Registration
ClinicalTrials.gov NCT02329444
doi:10.1371/journal.pone.0164256
PMCID: PMC5056748  PMID: 27723839
22.  Effect of remote ischemic preconditioning on cognitive function after off-pump coronary artery bypass graft: a pilot study 
Korean Journal of Anesthesiology  2013;65(5):418-424.
Background
Several studies have shown in animal models that remote ischemic preconditioning (rIPC) has a neuroprotective effect. However, a randomized controlled trial in human subjects to investigate the neuroprotective effect of rIPC after cardiac surgery has not yet been reported. Therefore, we performed this pilot study to determine whether rIPC reduced the occurrence of postoperative cognitive dysfunction in patients who underwent off-pump coronary artery bypass graft (OPCAB) surgery.
Methods
Seventy patients who underwent OPCAB surgery were assigned to either the control or the rIPC group using a computer-generated randomization table. The application of rIPC consisted of four cycles of 5 min ischemia and 5 min reperfusion on an upper limb using a blood pressure cuff inflating 200 mmHg before coronary artery anastomosis. The cognitive function tests were performed one day before surgery and again on postoperative day 7. We defined postoperative cognitive dysfunction as decreased postoperative test values more than 20% of the baseline values in more than two of the six cognitive function tests that were performed.
Results
In the cognitive function tests, there were no significant differences in the results obtained during the preoperative and postoperative periods for all tests and there were no mean differences observed in the preoperative and postoperative scores. The incidences of postoperative cognitive dysfunction in the control and rIPC groups were 28.6% (10 patients) and 31.4% (11 patients), respectively.
Conclusions
rIPC did not reduce the incidence of postoperative cognitive dysfunction after OPCAB surgery during the immediate postoperative period.
doi:10.4097/kjae.2013.65.5.418
PMCID: PMC3866337  PMID: 24363844
Cognitive disorders; Neuroprotective effect; Off-pump coronary artery bypass
23.  Remote ischemic preconditioning delays the onset of acute mountain sickness in normobaric hypoxia 
Physiological Reports  2015;3(3):e12325.
Acute mountain sickness (AMS) is a neurological disorder occurring when ascending too fast, too high. Remote ischemic preconditioning (RIPC) is a noninvasive intervention protecting remote organs from subsequent hypoxic damage. We hypothesized that RIPC protects against AMS and that this effect is related to reduced oxidative stress. Fourteen subjects were exposed to 18 hours of normoxia (21% oxygen) and 18 h of normobaric hypoxia (12% oxygen, equivalent to 4500 m) on different days in a blinded, randomized order. RIPC consisted of four cycles of lower limb ischemia (5 min) and 5 min of reperfusion, and was performed immediately before the study room was entered. A control group was exposed to hypoxia (12% oxygen, n = 14) without RIPC. AMS was evaluated by the Lake Louise score (LLS) and the AMS-C score of the Environmental Symptom Questionnaire. Plasma concentrations of ascorbate radicals, oxidized sulfhydryl (SH) groups, and electron paramagnetic resonance (EPR) signal intensity were measured as biomarkers of oxidative stress. RIPC reduced AMS scores (LLS: 1.9 ± 0.4 vs. 3.2 ± 0.5; AMS-C score: 0.4 ± 0.1 vs. 0.8 ± 0.2), ascorbate radicals (27 ± 7 vs. 65 ± 18 nmol/L), oxidized SH groups (3.9 ± 1.4 vs. 14.3 ± 4.6 μmol/L), and EPR signal intensity (0.6 ± 0.2 vs. 1.5 ± 0.4 × 106) after 5 h in hypoxia (all P < 0.05). After 18 hours in hypoxia there was no difference in AMS and oxidative stress between RIPC and control. AMS and plasma markers of oxidative stress did not correlate. This study demonstrates that RIPC transiently reduces symptoms of AMS and that this effect is not associated with reduced plasma levels of reactive oxygen species.
doi:10.14814/phy2.12325
PMCID: PMC4393159  PMID: 25742960
AMS; high altitude; oxidative stress; prevention; reactive oxygen species
24.  Remote ischemic precondition prevents radial artery endothelial dysfunction induced by ischemia and reperfusion based on a cyclooxygenase-2-dependent mechanism 
Ischemic preconditioning (IPC) and remote ischemic precondition (RIPC) are resistance to ischemia-reperfusion (IR) injury. They have common protective mechanism. Cyclooxygenase (COX)-2 participate in the mechanism of IPC. So, the purpose of this study was to determine whether RIPC protects endothelial function of radial artery in human against IR and whether COX-2 involves in this effect. Endothelial IR injury was induced by arm ischemia (20 min) and reperfusion. Flow-mediated dilation (FMD) of the radial artery was measured before and after IR. RIPC (three 5-min cycles of ischemia of the contralateral arm) was applied immediately and 24 h before IR. All volunteers received the COX-2 inhibitor celecoxib (200 mg orally twice daily) for 5 days. On day 6, all subjects experienced the same studies as described. FMD was reduced by IR without administration of RIPC (P<0.0001). RIPC prevent this impairment of FMD immediately (P=NS) and at 24 h (P=NS). Nevertheless, the COX-2 inhibiter abolished protective effect of RIPC at 24 h (P=NS), but not immediately (P=0.001). After administration of the COX-2 inhibiter, post-IR FMD after RIPC performed immediately had significant increase than after RIPC performed at 24 h (P=0.001) and without administration of RIPC (P=0.003). The COX-2 inhibiter made post-IR FMD evidently decrease after RIPC performed at 24 h (P=0.002). RIPC prevents radial artery endothelial dysfunction induced by IR. This protective effect of RIPC in the late phase is mediated by a COX-2-dependent mechanism.
PMCID: PMC4723868  PMID: 26885023
Remote ischemic preconditioning; endothelial function; ischemia and reperfusion; cyclooxygenase-2
25.  Activities of cardiac tissue matrix metalloproteinases 2 and 9 are reduced by remote ischemic preconditioning in cardiosurgical patients with cardiopulmonary bypass 
Background
Transient episodes of ischemia in a remote organ or tissue (remote ischemic preconditioning, RIPC) can attenuate myocardial injury. Myocardial damage is associated with tissue remodeling and the matrix metalloproteinases 2 and 9 (MMP-2/9) are crucially involved in these events. Here we investigated the effects of RIPC on the activities of heart tissue MMP-2/9 and their correlation with serum concentrations of cardiac troponin T (cTnT), a marker for myocardial damage.
Methods
In cardiosurgical patients with cardiopulmonary bypass (CPB) RIPC was induced by four 5 minute cycles of upper limb ischemia/reperfusion. Cardiac tissue was obtained before as well as after CPB and serum cTnT concentrations were measured. Tissue derived from control patients (N = 17) with high cTnT concentrations (≥0.32 ng/ml) and RIPC patients (N = 18) with low cTnT (≤0.32 ng/ml) was subjected to gelatin zymography to quantify MMP-2/9 activities.
Results
In cardiac biopsies obtained before CPB, activities of MMP-2/9 were attenuated in the RIPC group (MMP-2: Control, 1.13 ± 0.13 a.u.; RIPC, 0.71 ± 0.12 a.u.; P < 0.05. MMP-9: Control, 1.50 ± 0.16 a.u.; RIPC, 0.87 ± 0.14 a.u.; P < 0.01), while activities of the pro-MMPs were not altered (P > 0.05). In cardiac biopsies taken after CPB activities of pro- and active MMP-2/9 were not different between the groups (P > 0.05). Spearman’s rank tests showed that MMP-2/9 activities in cardiac tissue obtained before CPB were positively correlated with postoperative cTnT serum levels (MMP-2, P = 0.016; MMP-9, P = 0.015).
Conclusions
Activities of MMP-2/9 in cardiac tissue obtained before CPB are attenuated by RIPC and are positively correlated with serum concentrations of cTnT. MMPs may represent potential targets for RIPC mediated cardioprotection.
Trial registration
ClinicalTrials.gov identifier NCT00877305.
doi:10.1186/1479-5876-12-94
PMCID: PMC4234318  PMID: 24712447
Cardioprotection; Ischemia/reperfusion injury; Matrix metalloproteinases; Myocardial damage; Remote ischemic preconditioning

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